Cushing's disease - pasireotide
Cushing's disease is a rare condition, caused by an excessive level of corticosteroid hormones in the body, characterised by obesity, particularly in the trunk and face, fatigue, high blood pressure and a loss of calcium from the bones.
Cushing's disease is a rare condition, caused by an excessive level of corticosteroid hormones in the body, characterised by obesity, particularly in the trunk and face, fatigue, high blood pressure and a loss of calcium from the bones.
Novartis is developing pasireotide, a somatostatin analogue, as a potential treatment.
Its tolerability as a continuous subcutaneous infusion was investigated in healthy volunteers.1 They were given doses of 450µg to 2.25mg a day for seven days. Side-effects included abdominal discomfort, headache, nausea and altered stools. Some of the subjects given doses of at least 1.8mg experienced mild elevations in liver enzyme levels, and those given the highest doses had increased pancreatic enzymes.
In another study, 16 healthy subjects were given single doses ranging between 450µg and 1.5mg2. Loose stools, mild nausea and abdominal discomfort were among the side-effects experienced. It increased fasting glucose, and also decreased insulin and glucagon levels. Insulin levels returned to normal within four hours of dosing.
Its safety, tolerability and pharmacokinetics were also investigated in a group of 33 healthy male volunteers.3 A randomised double-blind placebo-controlled crossover study was carried out, in which placebo or 20, 200 or 600µg were given each day for 14 days. Drug concentrations increased in proportion to the dose, and no major side-effects were experienced.
Twelve patients with active acromegaly were given 100 or 250µg of pasireotide or 100µg octreotide in a double-blind randomised crossover clinical trial.4 All of the doses administered reduced serum GH levels within two to eight hours of each injection. It was highest with the larger dose of pasireotide and octreotide. The inhibitory efficacy was similar in both of these instances for eight patients. Three had a greater efficacy for pasireotide, and these differences were ascribed to differences in the expression of somatostatin receptor subtypes. All doses were well tolerated, which indicates that the new drug may have a positive effect on the long-term disease control of patients with acromegaly.
It is currenlty undergoing Phase II trials, and has potential as a treatment for solid tumours, because somatostatin receptors have now been found to be involved in cell proliferation and apoptosis.